End-stage Lung Disease from all causes is the fourth leading cause of death in the US. Despite the success of lung transplantation, demand for donor lungs has steadily outgrown supply. Currently, the average wait is 2 years, with 30% wait-list mortality. Likewise, acute respiratory distress syndrome (ARDS) is a predominant cause of death in trauma and critically ill patients. A paracorporeal artificial lung (PAL) was redesigned and built by MC3 (Ann Arbor, MI) in Phase I. The current PAL prototype in a pulmonary artery-to-pulmonary artery (PA-PA) configuration supported gas exchange in normal sheep (N=8) for up to 7 days. Additionally, 7/8 sheep achieved total gas exchange (02 and CO2) for 3 days following a lethal (LD100) smoke/burn injury. Our central hypothesis is that total extracorporeal gas exchange with the Optional Assisted Compliance Chamber (OACC) PAL will allow long-term respiratory support to achieve lung recovery from ARDS or bridge to lung transplant in patients with or without pulmonary hypertension. PHASE II Specific Aim 1: Develop an OACC to provide timed mechanical assist to right heart ejection. Since most patients with pulmonary disease have some degree of associated pulmonary hypertension, (often transiently severe) PAL must be able to provide total gas exchange (02 and CO2) and circulatory augmentation (primarily to the right ventricle). Specifically, using tightly coupled experimental and mathematical models (as outlined in the application); we will optimize the design of the OACC and PAL. The PAL will be able to overcome up to a 4-fold increase in pulmonary vascular resistance. We will determine the volume, pressure and cardiac cycle timing to optimize right ventricular support for application of PAL for pulmonary hypertension or right heart failure. Specific Aim 2" Design and fabricate injection molds for the preclinical production of PAL. Specific Aim 3: Utilizing our recently developed, clinically relevant LD100 sheep model of lethal ARDS, determine outcomes and measure injury parameters in two prospective randomized groups (N=10) over 10 days: 1) low tidal volume (LTV) ventilator management versus 2) PAL. Specific Aim 4: Investigate PAL impact on the pathophysiology of a lethal (LD100) smoke/burn induced lung injury randomized to PAL (N=10) or LTV ventilator management (N=10) then sacrifice at 48 degrees for full pathologic study. The knowledge gained will provide unique insight into the pathophysiology of ARDS and yield outcomes data for final PAL preclinical development.